Severe COVID-19 anxiety among adults in the UK: protocol for a cohort study and nested feasibility trial of modified cognitive–behavioural therapy for health anxiety

Introduction Some people are so anxious about COVID-19 that it impairs their functioning. However, little is known about the course of severe COVID-19 anxiety or what can be done to help people who experience it. Methods and analysis Cohort study with a nested feasibility trial with follow-up at 3 and 6 months. We recruited 306 people who were aged 18 and over, lived in the UK and had severe COVID-19 anxiety (indicated by a score of 9 or more on the Coronavirus Anxiety Scale (CAS)). To take part in the nested feasibility trial, participants also had to have a score of 20 or more on the Short Health Anxiety Inventory. We excluded people from the trial if they had had COVID-19 within the previous 4 weeks, if they were currently self-isolating or if they were already receiving psychological treatment. We publicised the study nationally through adverts, social media and posts on message boards. We also recruited participants via clinicians working in primary and secondary care NHS services in London. All those in the active arm will be offered 5–10 sessions of remotely delivered modified cognitive–behavioural therapy for health anxiety (CBT-HA). We will examine the proportion of participants who remain above threshold on the CAS at 3 and 6 months and factors that influence levels of COVID-19 anxiety over 6 months using mixed effects logistic regression. The key feasibility metrics for the nested trial are the level of uptake of CBT-HA and the rate of follow-up. Ethics and dissemination Approved by Leicester Central Research Ethics Committee (reference: 20/EM/0238). The results of the study will be published in peer-reviewed scientific journals. Trial registration number ISRCTN14973494.

multiple regression framework. First, regressions entail causal direction; are there previous evidence for any of the covariates to be causally linked with the predicted variable? If so, then could just as well skip this stepbut that would leave them with 10 covariates in a multiple regression, probably underpowered even if they focus only on main effects… My proposal would be to take a step back and acknowledge the very exploratory nature of this work and treat it as such. Preferably in a Bayesian framework which in my opinion is much more robust to handling exploratory work. The software JASP provides really simple tools for getting started with Bayesian analyses. 1) Provide a correlation matrix of all relationships. Make sure parametric assumptions are fulfilled, some covariates may not be suitable to include even after transformation.
2) Choose the covariates that fulfill a pre-defined evidence criteria for being related to the predicted variable (e.g., BF>3/10/20, depending on how conservative you want to be). Along with this, include variables that show evidence for possibly being indirectly related (could be moderators or mediators). 3) Run some multi-model inferences over a large model space and report the model averaged results. Also, look at whether a set of models are clearly more probable at explaining the data than other models. Remember to assert that parametric criteria are fulfilled. "Exploratory hypothesis tests to compare study groups will also be conducted. Linear regression will be used to compare mean difference in outcomes between groups, after adjusting for outcome scores at baseline. Mean differences between groups will be reported along with corresponding 95% confidence intervals. It is acknowledged that the study may be unpowered to show statistical significance, and so the feasibility of the trial will not be determined by the results of these tests." -Study group could be a used as a covariate in the above framework instead of running yet additional analyses.

Minor
At times, the concepts of Health Anxiety and Covid Anxiety are used almost interchangeably but as the authors themselved state, they are not one could have Covid Anxiety without having general Health Anxiety (but probably not the other way around). In the title they suggest they are looking at Health Anxiety, but the four objectives all state Covid Anxiety. However, the inclusion criteria holds that the participants must have both (>9 + >20): a) Please help the readers separate the two concepts (to the extent that they can be separated) better throughout all parts of the protocol. b) Of course too late to do something practical with now, but something that could be discussed is this "double" inclusion criteria (Covid Anxiety AND Health Anxiety). Of course, this is something they can look more at when studying the whole cohort, but then they should elaborate a bit more on that.
I don't see any problems with the criteria for determining the success of the feasibility study (80% of the target study sample, etc), but it would be nice if they offer either a short explanation or reference for why those exact criteria were chosen. Again, thank you for reviewing this important and promising worklooking forward to see how it progresses. Best regards, Philip Millroth Cited references: Sim, J. (2019). Should treatment effects be estimated in pilot and feasibility studies?. Pilot and feasibility studies, 5(1), 1-7.

REVIEWER
Spada, M London South Bank University, Psychology REVIEW RETURNED 12-Feb-2022

GENERAL COMMENTS
A study of this kind is of particular value in this moment in time. I commend the authors for wanting to undertake this line of research. I have a series of points for the authors to consider: (1) I am unclear if the sample has already been recruitedit appears to be the case. Please clarify.
(2) The link between COVID-19 anxiety and health anxiety is not well operationalised in your paper. Are you arguing that COVID-19 anxiety leads to health anxiety? There is contradictory evidence regarding this assumption. The bridge between COVID-19 anxiety and health anxiety needs to be strengthened to defend your position that adopting a CBT approach for health anxiety is the best course of action.
(3) The difficulty with utilising the Coronavirus Anxiety Scale (Lee, 2020) as an outcome is that you may experience a floor effect in terms of scores. Many individuals are not that anxious about the virus anymore (at least from the data coming in from our studies across continents). What they do display, however, is a set of behaviours best encapsulated by the COVID-19 anxiety syndrome (Nikcevic & Spada, 2020;Nikcevic et al., 2021;Albery et al., 2021). Indeed, these behaviours (avoidance, checking, ruminative thinking) are those that would be targeted by the modified CBT approach for health anxiety that you are proposing. Several researchers have argued that COVID-19 anxiety may be an outcome of such behaviours. An epiphenomenon. You could consider assessing the COVID-19 anxiety syndrome in your study.
(4) More detail on the adaptation of the CBT protocol from health anxiety needs to be provided. This brings us back to conceptualising what COVID anxiety is. A fear/anxiety response (Lee's concept) or a series of maladaptive behaviours that lock us into the fear/anxiety response (Nikcevic & Spada, 2020). The latter view is more closely aligned with CBT and metacognitive models of psychopathology.

GENERAL COMMENTS
Thank you for the interesting study protocol. Comments are attached in the document.

VERSION 1 -AUTHOR RESPONSE
Reviewer one (Millroth) 1) Adopting a Bayesian approach to analysing study data. > In response to this suggestion we have obtained additional statistical support from Paul Bassett of Stats Consultancy (www.statsconsultancy.co.uk). Dr Bassett helped us revise the analysis plan and we have thanked him for his contribution in the acknowledgments section of the paper. We have highlighted changes to the analysis plan on page 10 and page 11 of the revised manuscript. While we recognise the potential value of Bayesian approaches to analysing health data, we intend to use the more traditional frequentist approach to our analysis. This is also the approach recommended Dr Bassett and one that readers of BMJ Open will be more familiar with.
2) Clarification of the separation between the concepts of Health Anxiety and Covid Anxiety. > We have redrafted the introduction to the paper to provide more detailed descriptions of COVID, anxiety and health anxiety and explained how the dual aims of the study are to examine the prognosis of severe COVID anxiety and explore the feasibility of using a modified form of CBT for health anxiety for those who experience these problems.
3) I don't see any problems with the criteria for determining the success of the feasibility study > We have added a justification for thresholds used to judge whether a future explanatory trial would be feasible on page 10 of the manuscript.
Reviewer 2 (Spada) 1) To clarify whether the sample has already been recruited > The sample has already been recruited. At the start of the third paragraph on page six of the paper, we state that study recruitment ended in September 2021. We have not made any changes to the paper in relation to this feedback.
2) To provide greater justification of the plan to adopt CBT for health anxiety to try to help people COVID-19 anxiety > We have added text to the introduction section of the paper explaining that there were no evidence based approaches for helping people with severe COVID anxiety at the start of the pandemic and we selected this approach because of emerging evidence of high levels of health anxiety among people with COVID anxiety (page 3).
(3) The difficulty with utilising the Coronavirus Anxiety Scale (Lee, 2020) as an outcome is that you may experience a floor effect in terms of scores. Many individuals are not that anxious about the virus anymore (at least from the data coming in from our studies across continents). What they do display, however, is a set of behaviours best encapsulated by the COVID-19 anxiety syndrome (Nikcevic & Spada, 2020;Nikcevic et al., 2021;Albery et al., 2021). Indeed, these behaviours (avoidance, checking, ruminative thinking) are those that would be targeted by the modified CBT approach for health anxiety that you are proposing. Several researchers have argued that COVID-19 anxiety may be an outcome of such behaviours. An epiphenomenon. You could consider assessing the COVID-19 anxiety syndrome in your study. > We are not able to use the measure developed by Professor Spada and colleagues in this study as baseline data have already been collected. At the time of developing the protocol for this study Professor Spada had not published his work on the 'COVID-19 anxiety syndrome'. However, we fully agree that behaviours such as avoidance are important in understanding COVID anxiety and we did include questions about avoidance in the survey (please see page 8). We have also added the helpful references that were suggested by this reviewer.
(4) More detail on the adaptation of the CBT protocol from health anxiety needs to be provided. > One of the central aims of the feasibility trial is to learn in what ways the CBT-HA model may need to be modified to better support people with severe COVID anxiety. We will be analysing material recorded by the therapists about any modifications they make and we will present these findings alongside the results of the feasibility trial. We have added a sentence to the end of the section on study interventions to explain this (page 10 of the paper).
Reviewer 3 1) Please consider to add a short discussion to your protocol. > We have added a short discussion section as requested.
2) Reference numbers in the text should be inserted immediately after punctuation (with no word spacing) > We have corrected any instances where references were not cited in this way.
3) Abstract: -The specification of the planned number of study participants in the abstract is missing. > We have added this to the abstract 4) An interesting aspect of the introduction is how COVID-19 leads to increased anxiety in the population. Please provide appropriate references for the statements. Your argument will be clearer to the reader if you provide references and evidence. > We have added new references to the introduction highlighting findings of studies that have examined possible reasons for increased levels of anxiety during the course of the pandemic.

GENERAL COMMENTS
This study protocol presents a cohort study and nested feasibility study of modified cognitive behavioural therapy for health anxiety (CBT-HA) related to COVID. The study seems timely and empirically relevant as it examines the functionality of health anxiety response in the COVID pandemic. Furthermore, the essential of the feasibility of a randomised controlled trial of CBT-HA for people with severe COVID anxiety and health anxiety may lead to the implementation of a confirmatory trial to test the effectiveness that could improve mental health and social functioning.
I am pleased that the manuscript has gained in quality through the revision based on the reviewer feedback. I wish you continued success with your project.

VERSION 2 -AUTHOR RESPONSE
Point-by-point response to the Editor's comments and reviewer's comments > There are NO further reviewer comments Aside from the clean copy, please also provide a marked copy of your manuscript with 'tracked changes' and upload it under the file designation 'Main Documentmarked copy'. This is to show all the changes you have made for your paper. > Done Funder Grant# for NIHR Imperial Biomedical Research Centre: You have indicated a funder for your paper. Please ensure to provide an award/grant number for your funder in the main document file and in ScholarOne.

> Added
Please ensure that the funding statement in the ScholarOne system and main document should be the same. > Changed Please indicate the corresponding author on your title page along with his/her email address and affiliations. > Added Kindly place your table in the main text where the table is first cited. > Amended accordingly We have noticed that you have uploaded files under supplemental material. However, we cannot see any citation for the files within the main text. If the files need to be published as a supplementary file, please cite them as 'supplementary file' in the main text and re-upload the files in PDF format. > Added.
Kindly place your Authors' contribution, Acknowledgements, Funding Statement and Conflict of Interests Statement before your Reference list. > I do not understand this request -this IS ALREADY the format of the paper.